The purpose of this report is to determine the natural course of renal disease in non-insulin-dependent diabetes mellitus (NIDDM) in the Pima Indians and to identify the underlying pathogenetic mechanisms involved in the initiation and progression of renal disease in NIDDM. This project, in part, represents an extension of work previously reported as Project Number Z01 DK 69037. Glomerular function was characterized over a 5-year period in 194 Pima Indians selected to represent stages in the development and progression of diabetic renal disease. These studies revealed that glomerular filtration becomes elevated as NIDDM develops and increases for a number of years thereafter. It remains elevated while normo- or microalbuminuria persist, but declines progressively after the development of macroalbuminuria. The decline in glomerular filtration rate is predicted by albumin excretion and is due primarily to loss of intrinsic ultrafiltration capacity. Kidney biopsies were done in 51 of the Pima Indians who participated in the study described above. Subjects with newly-diagnosed NIDDM had greater glomerular volume than did Caucasians with normal kidneys. Those with diabetes of longer duration but no evidence of diabetic renal disease exhibited a further increase in glomerular volume, and a disproportionate share of the overall increase was attributable to enlargement of the mesangium. Those with microalbuminuria could not be distinguished from normoalbuminuria on structural grounds. By contrast, clinical nephropathy was associated with extensive structural changes, the most prominent of which was global sclerosis. In addition, clinical nephropathy was associated with a reduced number of podocytes per glomerulus, and the remaining podocytes were obliged to extend their foot processes in order to maintain the area covered. The role of parental hypertension in the development of proteinuria in the offspring and the impact of renal replacement therapy on survival in diabetic patients with end-stage renal disease were also examined.